The process of tumor dissemination or metastasis is an important aspect of clinical management of cancer. In most cases cancer patients with localized tumors have significantly better prognoses than those with disseminated tumors. The majority of cancer mortality has been associated with metastatic disease rather than the primary tumor. Since it has been estimated that 60-70% of patients have progressed to metastatic disease by the time of diagnosis better understanding of the factors leading to tumor dissemination is of vital importance. An enormous amount of research has been performed elucidating various components of this process. As a result a great deal is known about different molecules and pathways that are associated with metastatic progression, including activation of oncogenes, recruitment of metalloproteases, and motility factors. Despite this wealth of information, the critical initiating events or molecular pathways for tumor dissemination remain unclear. Part of the difficulty unraveling the complexity of metastasis may be due to multiple converging pathways associated with malignant potential. Another confounding factor is likely to be genetic modulation of the efficiency of tumor dissemination. Identification of key regulatory components of the metastatic process would serve two functions. First, they might provide more accurate prognostic markers of potential metastatic progression in patients than the current standards. Second, they may provide insights into the critical events in tumor dissemination, potentially leading to additional avenues of research or the development of novel therapies. My laboratory uses animal models for gene discovery and/or test hypotheses that are difficult or impossible to do in human populations, including direct experimental testing of epidemiological correlations. The focus of my laboratory is a combined genetics and genomics approach to determine how constitutional genetic composition influences susceptibility to malignant progression. The model studied is the highly aggressive, metastatic transgenic mammary tumor FVB/N-TgN(MMTV-PyVT)634Mul mouse, which develops pulmonary metastatic lesions in 85% of the animals by 100 days of age. By performing a breeding based strain survey, my laboratory demonstrated the first in vivo evidence that genetic background of the host is a major determinant of metastatic potential. Using quantitative trait genetic analysis of backcross or recombinant inbred mouse populations we subsequently mapped the location of a number of modifier genes in the mouse genome.More recently, my laboratory has been using a strategy we call "transomics" to begin to identify the genes that are responsible for the modulation of metastatic efficiency. Using a combination of haplotype mapping, gene expression profiling, proteomics, functional genomics, sequence analysis, and gene knock-down technologies we have been characterizing a number of interesting candidate genes. This approach has led to the recent characterization of the first of the metastasis efficiency modifier genes, Sipa1. Modulation of the function of this gene, either by a point mutation that alters the enzymatic efficiency of this molecule, or by modulating the relative amounts of this protein within the tumor cell, was shown to have significant impact on metastatic colonization of the lung. This was, to the best of our knowledge, the first direct example of a polymorphism influencing metastatic progression. In collaboration with Dr. Anton-Culver at UCI, we are currently performing preliminary human epidemiology studies to determine whether SIPA1 polymorphisms may also play a role in the efficiency of human breast cancer metastasis.In addition, my laboratory has been using our genetic and transomic resources to address a paradox that has arisen in the metastasis research community.